We observed that dexamethasone, a glucocorticosteroid, leads to an unanticipated enhancement of endothelial inflammatory mediator production by extracellular ATP. These effects are mediated in part by a direct effect on the purinergic receptor (P2Y2R) promoter, enhancing transcription of P2Y2R mRNA and protein expression. Inflammation promoting effects include enhanced release of IL-8 and increased transcription of adhesion molecules (ICAM-1, VCAM-1 and SELE). This positive feedback loop of glucocorticoids and ATP-induced endothelial inflammation highlights the observation that glucocorticoids are not uniformly immunosuppressive and has implications for understanding the interactions that occur between the purinergic receptors and ATP in the pathogenesis of vascular inflammation in shock syndromes or atherosclerosis. (J Pharmacol Exp Ther 2010;335:693) Dual specific phosphatases negatively regulate the effects of mitogen activated protein kinases. We show that dexamethasone, a glucocorticoid agonist and deoxycorticosterone, a mineralocorticoid agonist have novel effects on DUSP1 and DUSP5 expression and function. While qualitatively different, both dexamethasone and deoxycorticosterone induce DUSP1 and DUSP5 mRNA in endothelium. The enhanced expression of both DUSP1 and DUSP5 by these corticosteroids suppressed the responses of endothelial cells to TNF alpha. Notably, the induction of DUSP1 mRNA by either dexamethasone or deoxycorticosterone was suppressed by TNFalpha stimulation whereas induction of DUSP5 mRNA by either corticosteroid was not. The suppression of glucocorticoid induction of DUSP1 may be a mechanism by which TNFa amplifies endothelial inflammatory responses. COUP-TF-II is an orphan nuclear receptor that has essential roles in cardiovascular development and metabolic homeostasis. We investigated the effect of COUP-TF II on endothelial cell inflammatory responses. COUP-TFII mRNA expression is down-regulated by TNF alpha, while COUP-TFI is not affected. The down-regulation of COUP-TFII by TNF alpha is independent of MAPK pathways. COUP-TFII silencing increases TNF alpha-induced IL-6 mRNA expression and decreases TNF alpha-induced E-selectin. COUP TF II may represent a novel therapeutic target in conditions characterized by endovascular injury and inflammation such as acute lung injury or septic shock. This study is open for analysis only.
| Ding, Yi; Gao, Zhan-Guo; Jacobson, Kenneth A et al. (2010) Dexamethasone enhances ATP-induced inflammatory responses in endothelial cells. J Pharmacol Exp Ther 335:693-702 |
